Process for the synthesis of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanentriles

ABSTRACT

A novel process for producing a-[(dialkylamino)substituted-methylene]b-oxo-(substituted) propanenitriles of the formula: &lt;CHEM&gt; where R, R1 and R2 are defined in the specification by reacting a substituted isoxazole with a diaklylamide dimethylacetal is provided.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a process for the synthesis of α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds and to novel substituted isoxazole compounds useful as intermediates in the process.

2. Description of the Prior Art

The α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds are important intermediates for the preparation of therapeutic aryl and heteroaryl [7-(aryl and heteroaryl)pyrazolo(l,5-a)-pyrimidin-3-yl]methanone compounds which are useful as anxiolylic, antiepileptic, sedative-hypnotic and skeletal muscle relaxant agents. The aryl and heteroaryl [7-(aryl and hetroaryl)-pyrazolo [1,5-a] pyrimidin-3-yl]methanone compounds and uses for such compounds are described in U.S. Pat. No. 4,521,422, the contents of which are incorporated by reference.

In U.S. Pat. No. 4,900,836, the contents of which are incorporated by reference, a series of reactions in which the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds are utilized to produce the [7-(alkyl and hetroaryl)pyrazolo (1,5-a)-pyrimidin-3-yl]methanone compounds is described. This reference also describes the synthesis of the α-[(dialkylamino) substituted methylene]-β-oxo-(substituted) propanenitrile compounds via the reaction of a substituted acetonitrile with a dimethylformamide dimethylacetal.

It has now been found that α-[(dialkylamino) substituted methylene]β-oxo-(substituted) propane nitrile compounds may be advantageously synthesized via reaction of a substituted isoxazole with a dialkylamide dimethylacetal. The use of substituted isoxazole compounds in the production of α-[(dialkylamino)substituted methylene]-β-oxo(substituted)propanenitrile compounds has not been taught nor suggested by the art.

Certain substituted isoxazole compounds and their synthesis are known. For example, 5-(2,3,4,5-tetrafluorophenyl)-isoxazole (Chem. Abst. Registry No. 110985-65-4), 5-(2,4-dichloro-5-fluorophenyl) isoxazole (Registry No. 103318-74-6), 5-(2,3,-dichloro-phenyl) isoxazole (Registry No. 76344-98-4), 5-(5-nitro-2-furyl)-isoxazole (Registry No. 32332-91-5), 5-(4-methylphenyl)-isoxazole (Registry No. 7064-35-9), 5-(m-chloro phenyl) isoxazole (Registry No. 7064-34-8), 5-(m-bromo phenyl) isoxazole (Registry No. 7064-33-7), 5-(p-chloro-phenyl) isoxazole (Registry No. 7064-32-6), 5-(p-bromo phenyl) isoxazole (Registry No. 7064-31-5), N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-2-5-isoxazolyl)-3-thiophenesulfonamide (Registry No. 103118-33-8), 3-hydroxy-4-(5-isoxazolyl)-2(5H)-foranone (Registry No. 84-608-81-1) and 5-phenyl isoxazole (Registry No. 1006 -67-3) are known. Other substituted isoxazole compounds including those claimed herein are not known.

SUMMARY OF THE INVENTION

The invention provides an improved process for the large scale production of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds which may be represented by the following structural formula: ##STR2## wherein R is lower alkyl(C₁ -C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁ -C₃) and alkoxy(C₁ -C₃); phenyl di- or trisubstituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁ -C₃), methylenedioxy, alkylthio(C₁ -C₃), alkylsulfonyl(C₁ -C₃), amino, alkanoyl(C₁ -C₃), amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁ -C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁ -C₃), naphthalenyl, pyrazinyl, and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl (C₁ -C₃). The improved process comprises reacting an R₁ substituted isoxazole having the formula ##STR3## wherein R₁ is as defined above with a dialkylamide dimethylacetal having the formula ##STR4## wherein R and R² are as defined above at a temperature from about 50° C. to about 100° C. and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted) propanenitrile so produced. The invention also provides certain novel R₁ substituted isoxazole compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The process and compounds of the present invention are described in the following reaction scheme I: ##STR5##

In accordance with the above reaction scheme a 1-(cyclicsubstituted)ethanone (1), where R₁ is as described above, is reacted with dimethylformamide dimethyl acetal (2) for 15 hours at 50°-100° C. Evaporation and recrystallization gives the 3-dimethylamino-1-(substituted)-2-propen-1-one (3).

The 3-dimethylamino-1-(substituted)-2-propen-1-one compounds (3) and their synthesis are described in greater detail in U.S. Pat. No. 4,178,449 (col 2 lines 44-54), U.S. Pat. No. 4,281,000 (col 2 lines 28-34), and U.S. Pat. No. 4,236,005 (col 2 lines 45-54).

The 3-dimethylamino-1-(substituted)-2-propen-1-one (3) is reacted with hydroxylamine hydrochloride in absolute methanol for 2 hours at a temperature from about 50° to about 100° C. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. Concentration of the eluate gives the desired substituted isoxazole (5) which is reacted with a dialkylamide dimethylacetal (6) at a temperature from about 50° to about 100° C. for 4 hours. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. On cooling and/or concentrating the methylene chloride solution, the desired α-[(dialkylamino)substituted methylene]-β-oxo-(substituted) propanenitrile (7) crystallizes.

As described in U.S. Pat. No. 4,900,836, the α[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitriles find utility as intermediates in the preparation of therapeutic aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a)pyrimidin-3-yl] methanones. As described in U.S. Pat. No. 4,521,422 the aryl and heteroaryl [7-(aryl and heteroaryl)pyrazolo(l,5-a) pyrimidin-3-yl]methanones are useful as anxiolylic, antiepileptic, sedative-hypnotic, and skeletal muscle relaxant agents.

The above described process is an improvement over the procedure described in U.S. Pat. No. 4,900,836. The 1-(cyclicsubstituted)ethanones are readily available and inexpensive; the over all yields are higher; and the reaction work-ups are less labor and time intensive.

The following non-limiting examples illustrate the process of the present invention as well as the preparation of the novel compounds isoxazole intermediates.

EXAMPLE 1 3-Dimethylamino-1-(3-thienyl)-2-propen-1-one

A mixture of 48.4 g of 3-acetylthiophene and 75 ml of dimethylformamide dimethyl acetal, under nitrogen, is heated for 15 hours on a steam bath. The reaction is concentrated in vacuo and the residue crystallized from methylene chloride/hexane to give 60.55 g (87%) of the desired product, mp 89°-90° C.

Using the general procedure of Example 1, the following compounds of Example 2-26 shown in Table 1 are prepared.

                                      TABLE I                                      __________________________________________________________________________     Example                                                                             Starting Material                                                                            Compound             MP °C.                          __________________________________________________________________________      2   Acetophenone  3-dimethylaminoacrylophenone                                                                        93.0-94°                         3   2-Acetyl-5-bromothiophene                                                                    1-(5-bromo-2-thienyl)-3-dimethylamino-2-                                                            118-120°                                           propen-1-one                                                 4   4'-Chloroacetophenone                                                                        trans-4'-chloro-3-dimethylaminoacrylo-                                                              83-84°                                             phenone                                                      5   4'-Methoxyacetophenone                                                                       3-dimethylamino-4'-methoxyacrylophenone                                                             92-95°                           6   4'-Methylacetophenone                                                                        3-dimethylamino-4'-methylacrylophenone                                                              92.5-95°                         7   2-Acety-5-methylthiopene                                                                     1-(5-methyl-2-thienyl)-3-dimethylamino-2-                                                           113-115°                                           propen-1-one                                                 8   2-Acetylfuran 3-(dimethylamino)-1-(2-furyl)-2-propen-                                                             84-86°                                             1-one                                                        9   2-Acetyl-5-methylfuran                                                                       3-(dimethylamino)-1-(5-methyl-2-furanyl)-                                                           126-128°                                           2-propen-1-one                                              10   3'-Ethylacetophenone                                                                         3-(dimethylamino)-1-(3-ethylphenyl)-2-                                                              yellow orange                                             propen-1-one         viscous liquid                         11   4'-Nitroacetophenone                                                                         3-dimethylamino-4'-nitroacrylophenone                                                               150-151°                        12   2'-Fluoroacetophenone                                                                        ( .sub.-- E)-3-dimethylamino-2'-fluoroacrylophenone                                                 yellow oil                             13   4'-Fluoroacetophenone                                                                        trans-3-dimethylamino-4'-fluoroacrylo-                                                              96-97°                                             phenone                                                     14   1-Adamanyl methyl ketone                                                                     3-dimethylamino-1-tricyclo[3.3.1.1.sup.3,7 ]-                                                       142-143°                                           dec-1-yl-2-propen-1-one                                     15   4'-Acetylbiphenyl                                                                            3-dimethylamino-4'-phenylacrylophenone                                                                135-137.5°                    16   2'-Acetonaphthone                                                                            ( .sub.-- E)-3-dimethylamino-2'-acrylonaphthone                                                     96-98°                          17   3',4'-Dichloroacetophenone                                                                   trans-3',4'-dichloro-3-dimethylamino-                                                               94-95°                                             acrylophenone                                               18   3',4'-Dimethylacetophenone                                                                   3-dimethylamino-3' ,4'-dimethylacrylo-                                                              108-110°                                           phenone                                                     19   2',4'-Dichloroacetophenone                                                                   2',4'-Dichloro-3-dimethylaminoacrylo-                                                               83.5-85°                                           phenone                                                     20   2',6'-Difluoroacetophenone                                                                   1'-(2',6'-difluorophenyl)-3-(dimethyl-                                                              67-69°                                             amino)-2-propen-1-one                                       21   2-Acetyl-4-methylthiophene                                                                   3-(dimethylamino)-1-(4-methyl-2-thienyl)-                                                           102-104°                                           2-propen-1-one                                              22   3-Acetyl-1-methylpyrrole                                                                     3-(dimethylamino)-1-(1-methyl-1H-pyrrol-                                                            123-125°                                           3-yl)-2-propen-1-one                                        23   2-Acetylthiophene                                                                            3-dimethylamino-1-(2-thienyl)-2-propen-1-                                                           114-115°                                           one                                                         24   2-Acetyl-3-methylthiophene                                                                   ( .sub.-- E)-3-dimethylamino-1-(3-methyl-2-                                                         45-49°                                             thienyl)-2-propen-1-one                                     25   2',4'-Difluoroacetophenone                                                                   3-dimethylamino-2',4'-difluoroacrylo-                                                               48-49°                                             phenone                                                     26   2',5'-Difluoroacetophenone                                                                   3-dimethylamino-2',5'-difluoroacrylophenone                                                         66-67°                          __________________________________________________________________________

EXAMPLE 27

A mixture of 58.1 g of (3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 23.4 g of hydroxylamine hydrochloride and 250 ml of commercial absolute methanol is heated on a steam bath for 2 hours. The reaction is concentrated in vacuo, partitioned between methylene chloride and water and the organic layer dried over sodium sulfate. The methylene chloride is passed thru a short column of hydrous magnesium silicate and concentrated in vacuo to give 41.25 g (85%) of the desired product as a red-orange oil which solidified on standing. CI-MS: M/z 151(M⁺).

Using the general procedure of Example 27, the following compounds of Example 28-52, shown in Table II are prepared.

                  TABLE II                                                         ______________________________________                                                Starting                                                                       Material                                                                Example                                                                               of Example                                                                               Compound        MP °C.                                 ______________________________________                                         28      2        5-Phenylisoxazole                                                                              Colorless liquid                              29      3        5-(5-Bromo-2-thienyl)-                                                                         66-68°                                                  isoxazole                                                     30      4        5-( -p-Chlorophenyl)-                                                                          84-85°                                                  isoxazole                                                     31      5        5-( -p-Methoxyphenyl)-                                                                         64-65°                                                  isoxazole                                                     32      6        5- -p-Tolylisoxazole                                                                           60-61°                                 33      7        5-(5-Methyl-2-thienyl)-                                                                        30-32°                                                  isoxazole                                                     34      8        5-(2-Furanyl)isoxazole                                                                         Pale yellow oil                               35      9        5-(5-Methyl-2-furanyl)-                                                                        32-33°                                                  isoxazole                                                     36     10        5-(3-Ethylphenyl)isoxa-                                                                        Colorless liquid                                               zole                                                          37     11        5-(4-Nitrophenyl)isoxa-                                                                        172-174°                                                zole                                                          38     12        5-(2-Fluorophenyl)isoxa-                                                                       Yellow liquid                                                  zole                                                          39     13        5-(4-Fluorophenyl)isoxa-                                                                       52-53°                                                  zole                                                          40     14        5-Tricyclo[3.3.1.1..sup.3,7 ]-                                                                 32-33°                                                  dec-1-yl-isoxazole                                            41     15        5-[1,1'-Biphenyl]-4-yl-                                                                        130-132°                                                isoxazole                                                     42     16        5-(2-Naphthalenyl)isoxa-                                                                       110-112°                                                zole                                                          43     17        5-(3,4-Dichlorophenyl)-                                                                        88-89°                                                  isoxazole                                                     44     18        5-(3,4-Dimethylphenyl)-                                                                        46-47°                                                  isoxazole                                                     45     19        5-(2,4-Dichlorophenyl)-                                                                        127-129°                                                isoxazole                                                     46     20        5-(2,6-Difluorophenyl)-                                                                        63-64°                                                  isoxazole                                                     47     21        5-(4-Methyl-2-thienyl)-                                                                        pale yellow                                                    isoxazole       liquid                                        48     22        5-(1-Methyl-1 .sub.-- H-pyrrol-2-                                                              pale yellow                                                    yl)isoxazole    liquid                                        49     23        5-(2-Thienyl)isoxazole                                                                         dark yellow-                                                                   orange liquid                                 50     24        5-(3-Methyl-2-thienyl)-                                                                        pale yellow                                                    isoxazole       liquid                                        51     25        5-(2,4-Difluorophenyl)-                                                                        64-66°                                                  isoxazole                                                     52     26        5-(2,5-Difluorophenyl)-                                                                        74-77°                                                  isoxazole                                                     ______________________________________                                    

EXAMPLE 53 α-[(Dimethylamino)methylene]-β-oxo-3-thiophenepropanenitrile

A mixture of 41.2 g of 5-(3-thienyl)isoxazole and 36.0 g of dimethylformamide dimethylacetal, under nitrogen, is heated on a stream bath for 4 hours. The reaction is concentrated in vacuo to give a viscous oil which solidified. The residue is dissolved in methylene chloride and passed thru a short column of hydrous magnesium silicate. On cooling, 31.76 g of the desired product is obtained, mp 118°-119°, CI-MS:m/z 206(M³⁰). Concentrating in vacuo the methylene chloride gives an additional 20.2 g of product. (Total recovered 51.96 g, 92%).

Using the general procedure of Example 53, the following compounds of Example 54-78, shown in Table III are prepared.

                  TABLE III                                                        ______________________________________                                                Starting                                                                       Material                                                                Example                                                                               of Example                                                                               Compound         MP °C.                                ______________________________________                                         54     28        2-Benzoyl-3-dimethyl-                                                                           111-113°                                               aminoacrylonitrile                                            55     28        5-Bromo-α-[(dimethyl-                                                                     190-192°                                               amino)methylene]-β-oxo-2-                                                 thiophenepropanenitrile                                       56     29        2- -p-Chlorobenzoyl-3-                                                                          118-121°                                               dimethylaminoacrylo-                                                           nitrile                                                       57     30        α-[(Dimethylamino)methy-                                                                  107-110°                                               lene]-4-methoxy-β-oxo-                                                                     (dec)                                                         benzenepropanenitrile                                         58     31        α-[(Dimethylamino)methy-                                                                  132-135°                                               lene]-4-methyl-β-oxo-                                                     benzenepropanenitrile                                         59     32        α-[(Dimethylamino)-                                                                       151-153°                                               methyllene]-5-methyl-β-                                                   oxo-2-thiophenepropane-                                                        nitrile                                                       60     33        α-[(Dimethylamino)methy-                                                                  112-115°                                               lene]-β-oxo-2-furanpro-                                                   panenitrile                                                   61     34        α-[(Dimethylamino)-                                                                       135-137°                                               methyllene]-5-methyl-β-                                                   oxo-2-furanpropane-                                                            nitrile                                                       62     35        α-[(Dimethylamino)-                                                                       red-orange                                                    methylene]-3-ethyl-β-oxo-                                                                  oil                                                           benzenepropanenitrile                                         63     36        α-[(Dimethylamino)methy-                                                                  154-156°                                               lene]-4-nitro-β-oxo-                                                      benzenepropanenitrile                                         64     37        α-[(Dimethylamino)methy-                                                                  62-74°                                                 lene]-2-fluoro-β-oxo-                                                     benzenepropanenitrile                                         65     38        α-[(Dimethylamino)methy-                                                                  142-145°                                               lene]-4-fluoro-β-oxo-                                                     benzenepropanenitrile                                         66     39        α-[(Dimethylamino)methy-                                                                  183-189°                                               lene]-β-oxo-tricyclo-                                                     [3.3.1.1..sup.3,7 ]decane-1-                                                   propanenitrile                                                67     40        α-[(Dimethylamino)methy-                                                                  174-176°                                               lene]-β-oxo-4-biphenyl-                                                   propionitrile                                                 68     41        α-[(Dimethylamino)methy-                                                                  115-118°                                               lene]-β-oxo-2-naphthalene-                                                propanenitrile                                                69     42        3,4-Dichloro-α-[(dimethyl-                                                                130-142°                                               amino)methylene]-β-oxo-                                                   benzenepropanenitrile                                         70     43        α-[(Dimethylamino)methy-                                                                   82-112°                                               lene]-3,4-dimethyl-β-oxo-                                                 benzenepropanenitrile                                         71     44        2,4-Dichloro-α-[(dimethyl-                                                                yellow glass                                                  amino)methylene]-β-oxo-                                                   benzenepropanenitrile                                         72     45        α-[(Dimethylamino)methy-                                                                  109-111°                                               lene]-2,6-difluoro-β-oxo-                                                 benzenepropanenitrile                                         73     46        α-[(Dimethylamino)methy-                                                                  127-132°                                               lene]-4-methyl-β-oxo-2-                                                   thiophenepropanetrile                                         74     47        α-[(Dimethylamino)methy-                                                                   97-100°                                               lene]-1-methyl-β-oxo-1 .sub.-- H-                                         pyrrole-2-propanenitrile                                      75     48        α-[(Dimethylamino)methy-                                                                  136-140°                                               lene]-β-oxo-2-thiophene-                                                  propanenitrile                                                76     49        α-[(Dimethylamino)methy-                                                                  red-brown                                                     lene]-3-methyl-β-oxo-2-                                                                    viscous syrup                                                 thiophenepropanenitrile                                       77     50        α-[(Dimethylamino)methy-                                                                  137-139°                                               lene]-2,4-difluoro-β-oxo-                                                 benzenepropanenitrile                                         78     51        α-[(Dimethylamino)methy-                                                                  108-110°                                               lene]-2,5-difluoro-β-oxo-                                                 benzenepropanenitrile                                         ______________________________________                                     

We claim:
 1. A process for producing compounds of the formula: ##STR6## wherein R is lower alkyl (C₁ -C₃); R₁ is selected from the group consisting of phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁ -C₃) and alkoxy(C₁ -C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁ -C₃), methylenedioxy, alkylthio(C₁ -C₃), alkylsulfonyl(C₁ -C₃)-amino, alkanoyl (C₁ -C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁ -C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁ -C₃), naphthalenyl, pyrazinyl and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁ -C₃); which comprises:reacting a substituted isoxazole having the formula ##STR7## with dialkylamide dimethylacetal having the formula ##STR8## at a temperature from about 50° to about 100° C. and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced.
 2. The process of claim 1, wherein said substituted isoxazole is prepared by reacting a 3-dimethylamino-1-substituted-2-propen-1-one having the formula ##STR9## with hydroxylamine hydrochloride in absolute methanol at a temperature from about 50° C. to about 100° C.
 3. The process of claim 2 wherein said 3-dimethylamino-1-substituted 2-propen-1-one is prepared by reacting a 1-(cyclic substituted) ethanone having the formula ##STR10## with dimethylformamide dimethylacetal at a temperature of from about 50° C. to about 100° C.
 4. The process of claim 1, wherein α-[(dimethyl-amino)methylene]-β-oxo-3-thiophenepropanenitrile is produced.
 5. The process of claim 1, wherein 5-bromo-α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile is produced.
 6. The process of claim 1, wherein α-[(dimethylamino)methylene]-5-methyl-β-oxo-2-furanpropanenitrile is produced.
 7. The process of claim 1, wherein α-[(dimethylamino)methylene]-3-ethyl-β-oxo-benzenepropanenitrile is produced.
 8. The process of claim 1, wherein α-[(dimethylamino)methylene]-4-nitro-β-oxo-benzenepropanenitrile is produced.
 9. The process of claim 1, wherein α-[(dimethylamino)methylene]-β-oxo-tricyclo[3.3.1.1³,7 ]-decane-1-propanenitrile is produced.
 10. The process of claim 1, wherein α-[(dimethylamino)methylene]-β-oxo-4-biphenylpropanenitrile is produced.
 11. The process of claim 1, wherein 3,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile is produced.
 12. The process of claim 1, wherein α-[(dimethylamino)methylene]-3,4-dimethyl-β-oxo-benzenepropanenitrile is produced.
 13. The process of claim 1, wherein 2,4-dichloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanenitrile is produced.
 14. The process of claim 1, wherein α-[(dimethylamino)methylene]-2,6-difluoro-β-oxo-benzenepropanenitrile is produced.
 15. The process of claim 1, wherein α-[(dimethylamino)methylene]-4-methyl-β-oxo-2-thiophenepropanenitrile is produced.
 16. The process of claim 1, wherein α-[(dimethylamino)methylene]-1-methyl-β-oxo-1H-pyrrole-2-propanenitrile is produced..
 17. The process of claim 1, wherein α-[(dimethylamino)methylene]-3-methyl-β-oxo-2-thiophenepropanenitrile is produced.
 18. The process claim 1, wherein α-[(dimethylamino)methylene]-2,4-difluoro-β-oxo-benzenepropanenitrile is produced.
 19. The process of claim 1, wherein α-[(dimethylamino)methylene]-2,5-difluoro-β-oxo-benzenepropan-enitrile is produced. 